Score

Autism Reports / Total Reports

Rare Variants / Common Variants

Aliases

Associated Syndromes

-

Genetic Category

Rare Single Gene Mutation, Syndromic, Genetic Association

Chromosome Band

20q13.33

Associated Disorders

ADHD, ASD, DD/NDD, ID

Relevance to Autism

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband (who also carried a maternally-inherited AFF2 missense variant); this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013).

Molecular Function

The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1).

SFARI Gene score

Suggestive Evidence

Score Delta: Increased from 3 to 4.4 + acc2

criteria met

Suggestive Evidence

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

Reports Added

10/1/2017

3

3

Increased from 3 to 3

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Reports Added

4/1/2017

3

3

Increased from 3 to 3

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

1/1/2017

3

3

Increased from 3 to 3

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Reports Added

10/1/2016

3

3

Increased from 3 to 3

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Reports Added

7/1/2016

3

3

Increased from 3 to 3

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Reports Added

1/1/2016

3

3

Increased from 3 to 3

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

7/1/2015

3

Increased from to 3

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Krishnan Probability Score

Score 0.61544698513644

Ranking 116/25841 scored genes

[Show Scoring Methodology]

Krishnan and colleagues generated probability scores genome-wide by using a machine learning
approach on a human brain-specific gene network. The method was first presented in Nat
Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed
in column G of supplementary table 3 (see:
http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser,
with the ability to view networks of associated ASD risk genes, can be found at
asd.princeton.edu.

ExAC Score

Score 0.99935609863785

Ranking 983/18225 scored genes

[Show Scoring Methodology]

The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has
been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by
Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at
exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of-
function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of-
function mutations in autism in such a gene would be more likely to confer risk. For a full list of
pLI scores see:
ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle
aned_exac_nonTCGA_z_pli_rec_null_data.txt

Sanders TADA Score

Score 0.35217872398636

Ranking 225/18665 scored genes

[Show Scoring Methodology]

The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013),
and is a statistic that integrates evidence from both de novo and transmitted mutations.
It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233
(2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper
(the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).

Larsen Cumulative Evidence Score

Score 15.5

Ranking 126/461 scored genes

[Show Scoring Methodology]

Larsen and colleagues generated gene scores based on the sum of evidence for all available
ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size,
and variant frequency in the general population. The approach was first presented in Mol Autism
7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from
that paper.

Zhang D Score

Score 0.30659428508961

Ranking 2638/20870 scored genes

[Show Scoring Methodology]

The DAMAGES score (disease-associated mutation analysis using gene expression signatures),
or D score, was developed to combine evidence from de novo loss-of- function mutation with
evidence from cell-type- specific gene expression in the mouse brain (specifically translational
profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with
positive D scores are more likely to be associated with autism risk, with higher-confidence genes
having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204-
215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in
supplementary table 2 from that paper.